The fundamental premise of our application is to provide unbiased, non-hypothesis driven, analysis of immune signatures (IMS) associated with human disease. We will elucidate whether specific IMS are associated with preferential expansion/contraction of certain defined subsets which are already physiologically and homeostatically present within the individual's T cell pool, and which largely maintain their characteristic IMS. We will also consider the alternative, and not mutually exclusive, possibility that changes in IMS reflect generation of distinct T cell subsets with differentiation / activation states uniquely associated with infection, disease and vaccination. Addressing these issues in different human pathogen systems and in different geographical locations, it will be possible to establish to what extent the results obtained are generally applicable. Accordingly, we propose to characterize CD4 and CD8 memory T cell IMS associated with Mycobacterium tuberculosis (MTB) and dengue virus (DENV) in the context of 1) natural immunity and/or control of infection, 2) active and severe disease and 3) administration of licensed or experimental vaccines. Our group has studied MTB and DENV for several years for the following reasons. 1.They are both current global health problems. 2. For these diseases memory T cells are fundamentally associated with protective immunity. 3. Antigen-specific T cell responses are detected in sufficient numbers ex vivo, allowing omics study without the need for in vitro expansion or stimulation. 4. Human specimens associated with natural infection/immunity and severe diseases are easily accessible in large numbers. As a result, we have developed a critical mass that is extensively leveraged herein, based on: 1) an established team of experienced LJI investigators, 2) established clinical collaborations with leaders in the field, ensuring that the goal of recruitment of large numbers of suitably characterized individuals will be met (in fact, hundreds of samples are already available), 3) hundreds of epitopes restricted by a variety different HLA class I and II molecules to allow an analysis of memory T cells of unprecedented precision 4) existing data identifying specific T cell subsets as key players in immunity and 5) established and well validated micro- scaled omics assays for generating IMC related to MTB and DENV. The HIPC format is ideally suited to accomplish the proposed mission. Each project and core is critically dependent on other elements of the program. Only in the context of HIPC will we be able to realize the synergies, benefit from an economy of scale and operation, and bring different groups of investigators with different expertise together in a well and organized plan.